[ CAS No. 3987-92-6 ] {[proInfo.proName]}

Name: 3987-92-6|Methyl 4-amino-3-nitrobenzoate|95%
Brand: Ambeed
SKU: A390084
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Quality Control of [ 3987-92-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 3987-92-6 ]

Product Details of [ 3987-92-6 ]

CAS No. :	3987-92-6	MDL No. :	MFCD00017562
Formula :	C₈H₈N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HNTLUEZVPLRQEV-UHFFFAOYSA-N
M.W :	196.16	Pubchem ID :	3941008
Synonyms :

Calculated chemistry of [ 3987-92-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.95
TPSA :	98.14 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.45
Log Po/w (XLOGP3) :	1.06
Log Po/w (WLOGP) :	0.97
Log Po/w (MLOGP) :	0.3
Log Po/w (SILICOS-IT) :	-1.14
Consensus Log Po/w :	0.53

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.84
Solubility :	2.81 mg/ml ; 0.0144 mol/l
Class :	Very soluble
Log S (Ali) :	-2.71
Solubility :	0.381 mg/ml ; 0.00194 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.5
Solubility :	6.2 mg/ml ; 0.0316 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.01

Safety of [ 3987-92-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 3987-92-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 3987-92-6 ]
Downstream synthetic route of [ 3987-92-6 ]

[ 3987-92-6 ] Synthesis Path-Upstream 1~8

1
[ 3987-92-6 ]
[ 36692-49-6 ]

Reference： [1] Journal of the Chemical Society, 1957, p. 2197,2199
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, # 1-12, p. 1106 - 1109
[3] Chinese Chemical Letters, 2017, vol. 28, # 4, p. 919 - 926

2
[ 67-56-1 ]
[ 1588-83-6 ]
[ 3987-92-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 20℃; for 16 h; Heating / reflux	To a suspension of 4-amino-3-nitrobenzoic acid (50 g, 270 mmol, 1 equiv) in MEOH (600 mi) at room temperature was added SOCI2 (20 ML, 270 mmol, 1 equiv) dropwise. The resulting suspension was refluxed for 16 h then cooled to room temperature. The suspension was filtered off to give methyl-4-amino-3-nitrobenzoate (D1) (53g, 100percent) as a yellow solid which was used in the next step without further purification. [M+H] + = 197.3, RT = 2. 42 min.
100%	for 16 h; Heating / reflux	Description 1Methyl 4-amino-3-nitrobenzoate (D1); To a suspension of 4-amino-3-nitrobenzoic acid (available commercially from Aldrich) (50 g, 270 mmol, 1 equiv) in MeOH (600 ml) at room temperature was added SOCI₂ (20 ml, 270 mmol, 1 equiv) dropwise. The resulting suspension was refluxed for 16 h then cooled to room temperature. The suspension was filtered off to give methyl-4-amino-3- nitrobenzoate (D1) (53g, 100percent) as a yellow solid which was used in the next step without further purification. [M+H]⁺ = 197.3, RT = 2.42 min.
100%	at 0℃; for 12 h; Reflux	Preparaton ofJ^-(4-(methoxymethyl)-2-nitrophenyl)~lS^-methylpyrM a. methyl 4-amino-3-nitrobenzoate Thionyl chloride (19.4g, 164.85 mmol) was added to a solution of 4-amino-3-nitrobenzoic acid (20g, 109.89 mmol) in methanol (200mL) at 0 °C. The resulting mixture was then refiuxed for 12h. The reaction mixture was allowed to cool to room temperature. The yellow solid precipitated was filtered and dried to afford the title compound (22g, yield: 100percent) as a solid. IH- NMR (CDC1₃, 300MHz): δ 8.85 (d, IH), 7.99 (dd, IH), 6.83 (d, IH), 6.40 (s, 2H), 3.90 (s, 3H).

89.2%	at 0 - 50℃; for 4.5 h;	4-aminobenzoic acid (i.e., compound 1.4.50 g, 24.7 mmol), anhydrous methanol (80 mL),(5.38 mL, 74.1 mmol, 3 equiv) was slowly added dropwise with a constant-pressure dropping funnel. After completion of the dropwise addition, the mixture was further stirred at 0 ° C for 30 minutes, and the mixture was cooled to 0 ° C. , Heated to 50 reaction 4h, a large number of yellow solids generated, filtration, the filtrate of methanol evaporated, add 30mL of water and 30mL of ethyl acetate, liquid, dry the organic layer with anhydrous sodium sulfate, evaporated solvent To give a yellow solid which was combined with the previous filter cake and dried to give compound 2a as a yellow solid, 4.32 g, 89.2percent yield. Melting point: 181.9-182.7 ° C.
89.2%	at 0 - 50℃; for 4.5 h;	The commercial compound 4 (4.50g, 24.7mmol) was dissolved in methanol (80mL). The reaction was cooled to 0°C, and thionyl chloride (5.38mL, 74.1mmol, 3 equiv) was added dropwise. The reaction mixture was stirred at 0°C for 30min and was heated to 50°C for 4h. The precipitate formed on cooling was collected by filtration. The solvent was removed under reduced pressure. The residue was dissolved with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, and the solvent was removed by evaporation. The yellow solid was combined. Methyl 4-amino-3-nitrobenzoate (5a). Yield: 89.2percent, yellow solid, mp 181.9-182.7 °C. ¹H NMR (300 MHz, CDCl₃) δ 8.85 (d, J = 1.9 Hz, 1H), 7.99 (dd, J = 8.8, 1.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.42 (brs, 2H), 3.90 (s, 3H). IR (KBr) (ν_max/cm^-1): 3475, 3343, 3030, 2961, 2855, 1702, 1634, 1565, 1522, 1477, 1356, 1298, 1262, 1133, 832, 760. MS (ESI) [M+H] ⁺ 197.06.
81%	Reflux	Step 1 4-Amino-3-nitro-benzoic acid methyl esterTo a mixture of 4-amino-3-nitro-benzoic acid (10.0 g, 54.9 mm0l) suspended in methanol (150 mL) was added thionyl chloride (3.99 mL, 54.9 mmol). The mixture was heated to reflux overnight, then cooled to room temperature and filtered. The solid recovered by filtration was rinsed with cold methanol and dried to give 8.68 g (81percent) of 4-amino-3-nitro-benzoic acid methyl ester.

Reference： [1] Patent: WO2004/94430, 2004, A1, . Location in patent: Page 16
[2] Patent: WO2006/40148, 2006, A1, . Location in patent: Page/Page column 19-20
[3] Patent: WO2015/57938, 2015, A1, . Location in patent: Page/Page column 102
[4] Patent: CN106146416, 2016, A, . Location in patent: Paragraph 0046; 0047; 0048; 0049; 0050
[5] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 8 - 20
[6] Patent: US2010/324070, 2010, A1, . Location in patent: Page/Page column 21
[7] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, # 1-12, p. 1106 - 1109
[8] Synlett, 2005, # 20, p. 3071 - 3074
[9] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 5, p. 2106 - 2119
[10] Synthesis, 2006, # 20, p. 3467 - 3477
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6156 - 6174
[12] Chinese Chemical Letters, 2017, vol. 28, # 4, p. 919 - 926

3
[ 1588-83-6 ]
[ 3987-92-6 ]

Reference： [1] Patent: US6166218, 2000, A,

4
[ 53178-59-9 ]
[ 3987-92-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6995 - 7004

5
[ 865-47-4 ]
[ 618-95-1 ]
[ 3816-62-4 ]
[ 3987-92-6 ]

Reference： [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888

6
[ 618-95-1 ]
[ 118535-52-7 ]
[ 3816-62-4 ]
[ 3987-92-6 ]

Reference： [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888

7
[ 618-95-1 ]
[ 3816-62-4 ]
[ 3987-92-6 ]

Reference： [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888

8
[ 3987-92-6 ]
[ 77-78-1 ]
[ 36242-50-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With sodium hydroxide; potassium carbonate In toluene at 40℃; for 1 h; Stage #2: for 2 h;	(Intermediate Example 69) 1-Methyl-1H-benzimidazole-5-carboxylic acid Methyl 4-amino-3-nitrobenzoate (7.0 g), sodium hydroxide (5.7 g), potassium carbonate (4.9 g) and tetrabutylammonium bromide (0.22 g) were suspended in toluene (100 ml). The mixture was stirred for 1 hour at 40°C, and then dimethylsulfuric acid (7. 7 ml) was added thereto and stirred for 2 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give methyl 4-methylamino-3-nitrobenzoate (7.3 g, Y.: 97percent). ¹H NMR; (DMSO-d₆) δ (ppm): 3.0 (d, 3H), 3.8 (s, 3H), 7.0 (d, 1H), 8.00 (dd, 1H), 8.5-8.7 (brs, 1H), 8.6 (d, 1H). ESI/MS (m/z): 325 (M+H)⁺, 323 (M-H)^-.

Reference： [1] Patent: EP1595866, 2005, A1, . Location in patent: Page/Page column 26

[ 3987-92-6 ] Synthesis Path-Downstream 1~88

1
[ 3987-92-6 ]
[ 36692-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 3h;	General procedure: 1 g (4.7 mmol) s2 was dissolved in 25 mL ethyl acetate, 15 mg 10%Pd/C was added. The mixture was stirred at room temperature for 3 h under hydrogen atmosphere. The filtrate was concentrated by vacuum distillation to obtain pale green oil of s3 800 mg, yield 93%.MS calcd. for: C9H12N2O2: 180.09, GC/MS: 180.

Reference： [1]Journal of the Chemical Society,1957,p. 2197,2199
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1988,vol. 27,p. 1106 - 1109
[3]Chinese Chemical Letters,2017,vol. 28,p. 919 - 926
[4]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1597 - 1600

2
[ 67-56-1 ]
[ 1588-83-6 ]
[ 3987-92-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; at 20℃; for 16h;Heating / reflux;	To a suspension of 4-amino-3-nitrobenzoic acid (50 g, 270 mmol, 1 equiv) in MEOH (600 mi) at room temperature was added SOCI2 (20 ML, 270 mmol, 1 equiv) dropwise. The resulting suspension was refluxed for 16 h then cooled to room temperature. The suspension was filtered off to give methyl-4-amino-3-nitrobenzoate (D1) (53g, 100%) as a yellow solid which was used in the next step without further purification. [M+H] + = 197.3, RT = 2. 42 min.
100%	With thionyl chloride; for 16h;Heating / reflux;	Description 1Methyl 4-amino-3-nitrobenzoate (D1); To a suspension of 4-amino-3-nitrobenzoic acid (available commercially from Aldrich) (50 g, 270 mmol, 1 equiv) in MeOH (600 ml) at room temperature was added SOCI2 (20 ml, 270 mmol, 1 equiv) dropwise. The resulting suspension was refluxed for 16 h then cooled to room temperature. The suspension was filtered off to give methyl-4-amino-3- nitrobenzoate (D1) (53g, 100%) as a yellow solid which was used in the next step without further purification. [M+H]+ = 197.3, RT = 2.42 min.
100%	With thionyl chloride; at 0℃; for 12h;Reflux;	Preparaton ofJ^-(4-(methoxymethyl)-2-nitrophenyl)~lS^-methylpyrM a. methyl 4-amino-3-nitrobenzoate Thionyl chloride (19.4g, 164.85 mmol) was added to a solution of 4-amino-3-nitrobenzoic acid (20g, 109.89 mmol) in methanol (200mL) at 0 C. The resulting mixture was then refiuxed for 12h. The reaction mixture was allowed to cool to room temperature. The yellow solid precipitated was filtered and dried to afford the title compound (22g, yield: 100%) as a solid. IH- NMR (CDC13, 300MHz): delta 8.85 (d, IH), 7.99 (dd, IH), 6.83 (d, IH), 6.40 (s, 2H), 3.90 (s, 3H).

97%	With sulfuric acid; for 24h;Reflux;	Toa solution of 4-amino-3-nitrobenzoic acid (11, 500 mg, 2.75 mmol) inMeOH (20 mL), a catalytic amount of concentrated sulfuric acid was added in a dropwisefashion. The mixture was heated at reflux temperature overnight. After beingcooled, the reaction was quenched by saturated NaHCO3solution andextracted by ethyl acetate.The organic layer was separated and dried over anhydroussodium sulfate. Filtration and concentrationin vacuogave 12 (519 mg, 97%); yellow solid;deltaH(300 MHz; MeOD),8.75 (1H, d, J = 2.1 Hz), 7.93 (1H, dd, J = 8.7, 2.1Hz), 7.02 (1H, d, J = 8.7 Hz), 3.91 (3H, s);deltaC (75 MHz; MeOD), 165.83, 148.90,134.71, 128.28, 118.56, 117.05, 51.10; MS (ESI) m/z 197.0(MH+).
89.2%	With thionyl chloride; at 0 - 50℃; for 4.5h;	4-aminobenzoic acid (i.e., compound 1.4.50 g, 24.7 mmol), anhydrous methanol (80 mL),(5.38 mL, 74.1 mmol, 3 equiv) was slowly added dropwise with a constant-pressure dropping funnel. After completion of the dropwise addition, the mixture was further stirred at 0 C for 30 minutes, and the mixture was cooled to 0 C. , Heated to 50 reaction 4h, a large number of yellow solids generated, filtration, the filtrate of methanol evaporated, add 30mL of water and 30mL of ethyl acetate, liquid, dry the organic layer with anhydrous sodium sulfate, evaporated solvent To give a yellow solid which was combined with the previous filter cake and dried to give compound 2a as a yellow solid, 4.32 g, 89.2% yield. Melting point: 181.9-182.7 C.
89.2%	With thionyl chloride; at 0 - 50℃; for 4.5h;	The commercial compound 4 (4.50g, 24.7mmol) was dissolved in methanol (80mL). The reaction was cooled to 0C, and thionyl chloride (5.38mL, 74.1mmol, 3 equiv) was added dropwise. The reaction mixture was stirred at 0C for 30min and was heated to 50C for 4h. The precipitate formed on cooling was collected by filtration. The solvent was removed under reduced pressure. The residue was dissolved with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and the solvent was removed by evaporation. The yellow solid was combined. Methyl 4-amino-3-nitrobenzoate (5a). Yield: 89.2%, yellow solid, mp 181.9-182.7 C. 1H NMR (300 MHz, CDCl3) delta 8.85 (d, J = 1.9 Hz, 1H), 7.99 (dd, J = 8.8, 1.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.42 (brs, 2H), 3.90 (s, 3H). IR (KBr) (numax/cm-1): 3475, 3343, 3030, 2961, 2855, 1702, 1634, 1565, 1522, 1477, 1356, 1298, 1262, 1133, 832, 760. MS (ESI) [M+H] + 197.06.
81%	With thionyl chloride;Reflux;	Step 1 4-Amino-3-nitro-benzoic acid methyl esterTo a mixture of 4-amino-3-nitro-benzoic acid (10.0 g, 54.9 mm0l) suspended in methanol (150 mL) was added thionyl chloride (3.99 mL, 54.9 mmol). The mixture was heated to reflux overnight, then cooled to room temperature and filtered. The solid recovered by filtration was rinsed with cold methanol and dried to give 8.68 g (81%) of 4-amino-3-nitro-benzoic acid methyl ester.
	With sulfuric acid; for 6h;Reflux;	General procedure: Synthesis of methyl 4-(methylamino)-3-nitrobenzoate (s2):3.6 g (18 mmol) 4-methylamino-3-nitro-benzoic acid (s1) was dissolved in 35 mL methanol, 1 mL concentrated sulfuric acid was added. The mixture was heated and maintained at reuxing temperature of 70C for 6 h, then cooled and poured into 100 mL water, neutralized with saturated solution of sodium bicarbonate, extracted with 100 mL ethyl acetate, washed with 50 mL water and dried with anhydrous sodium sulfate overnight. The filtrate was concentrated by vacuum distillation to obtain yellow solid of s2 3 g,yield 77%. MS calcd. for: C9H10N2O4: 210.06, GC/MS: 210.

Reference： [1]Patent: WO2004/94430,2004,A1 .Location in patent: Page 16
[2]Patent: WO2006/40148,2006,A1 .Location in patent: Page/Page column 19-20
[3]Patent: WO2015/57938,2015,A1 .Location in patent: Page/Page column 102
[4]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1173 - 1176
[5]Patent: CN106146416,2016,A .Location in patent: Paragraph 0046; 0047; 0048; 0049; 0050
[6]European Journal of Medicinal Chemistry,2018,vol. 143,p. 8 - 20
[7]Patent: US2010/324070,2010,A1 .Location in patent: Page/Page column 21
[8]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1988,vol. 27,p. 1106 - 1109
[9]Synlett,2005,p. 3071 - 3074
[10]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119
[11]Synthesis,2006,p. 3467 - 3477
[12]Journal of Medicinal Chemistry,2013,vol. 56,p. 6156 - 6174
[13]Chinese Chemical Letters,2017,vol. 28,p. 919 - 926

3
[ 865-47-4 ]
[ 618-95-1 ]
[ 3816-62-4 ]
[ 3987-92-6 ]
2-Amino-5-nitro-benzoic acid tert-butyl ester [ No CAS ]
3-Nitro-N-(pyrrolidine-1-carbothioylsulfanyl)-benzamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 4878 - 4888

4
[ 618-95-1 ]
[ 118535-52-7 ]
[ 3816-62-4 ]
[ 3987-92-6 ]
2-Amino-5-nitro-benzoic acid tert-butyl ester [ No CAS ]
3-Nitro-N-(pyrrolidine-1-carbothioylsulfanyl)-benzamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 4878 - 4888

5
[ 618-95-1 ]
[ 3816-62-4 ]
[ 3987-92-6 ]
2-Amino-5-nitro-benzoic acid tert-butyl ester [ No CAS ]
3-Nitro-N-(pyrrolidine-1-carbothioylsulfanyl)-benzamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 4878 - 4888

6
[ 3987-92-6 ]
[ 105655-17-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With bromine; In dichloromethane; at 20℃; for 3h;Heating / reflux;	To a solution of methyl-4-amino-3-nitrobenzoate (D1) (48 g, 244 mmol, 1 equiv) in CH2CI2 (1.4 I) at room temperature was added bromine (16.3 ML, 318 mmol, 1.3 equiv). The resulting solution was refluxed for 2 h then another 6 ml (117 mmol, 0.5 equiv) of bromine were added and the solution was stirred for 1 h then cooled to room temperature. The organic phase was washed twice with a 10% sodium thiosulfite aqueous solution (200 ml) then with H2O (200 ML), dried over MGS04 and concentrated in vacuo to give methyl 4-amino-3-bromo-5-nitrobenzoate (D2) (66.2 g, 98%) as a yellow solid which was used in the next step without further purification. [M-H]-= 274.1, RT = 2.90 min.
	With bromine; In dichloromethane; at 20℃; for 3h;Heating / reflux;	Description 2 Methyl 4-amino-3-bromo-5-nitrobenzoate (D2); To a solution of methyl-4-amino-3-nitrobenzoate (may be prepared as described in Description 1) (48 g, 244 mmol, 1 equiv) in CH2CI2 (1.4 I) at room temperature was added bromine (16.3 ml, 318 mmol, 1.3 equiv). The resulting solution was refluxed for 2 h then another 6 ml (117 mmol, 0.5 equiv) of bromine were added and the solution was stirred for 1 h then cooled to room temperature. The organic phase was washed twice with a 10% aqueous sodium thiosulfite solution (200 ml) then with H2O (200 ml), dried over MgSO4 and concentrated in vacuo to give methyl 4-amino-3-bromo-5-nitrobenzoate (D2) (66.2 g, 98%) as a yellow solid which was used in the next step without further purification. [M-H]" = 274.1 , RT = 2.90 min.

Reference： [1]Synlett,2005,p. 3071 - 3074
[2]Patent: WO2004/94430,2004,A1 .Location in patent: Page 16
[3]Synthesis,2006,p. 3467 - 3477
[4]Patent: WO2006/40148,2006,A1 .Location in patent: Page/Page column 19

7
[ 3987-92-6 ]
[ 103-80-0 ]
[ 928850-32-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

8
[ 3987-92-6 ]
[ 100-39-0 ]
[ 68502-46-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

9
[ 3987-92-6 ]
[ 172221-28-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With iodine; silver sulfate; In ethanol; at 20℃;	Step 2 4-Amino-3-iodo-5-nitro-benzoic acid methyl esterTo a solution of <strong>[3987-92-6]4-amino-3-nitro-benzoic acid methyl ester</strong> (4.6 g, 23.45 mmol) in ethanol (120 mL) was added iodine (8.33 g, 32.83 mmol), followed by Ag2SO4 (10.24 g 32.83 mmol). The mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give 4.98 g (66%) of 4-amino-3-iodo-5-nitro-benzoic acid methyl ester.
8.08 g	With iodine; silver sulfate; In methanol; at 20℃; for 12h;	Add iodine (9.70g, 38.23mmol) to a 500mL eggplant-shaped bottle, and then add 250mL of methanol to the bottle to dissolve the iodine, and then add silver sulfate (11.92g, 38.23mmol) and A6 (5.00g, 25.49mmol) in order. Stir at room temperature for 12 hours. After the reaction was detected by TLC, it was filtered and the reaction solvent was distilled off. After the residue was diluted with dichloromethane (100 mL), a saturated sodium thiosulfate solution (100 mL) was added, and then extracted with dichloromethane (100 mL × 3), dried over anhydrous sodium sulfate, the drying agent was filtered, and the crude product was concentrated. The crude product was separated by silica gel column chromatography (dichloromethane as the eluent) to obtain 8.08 g of an orange-yellow solid with a yield of 98%.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3669 - 3673
[2]Patent: US2010/324070,2010,A1 .Location in patent: Page/Page column 21
[3]Synthesis,2006,p. 3467 - 3477
[4]Patent: CN110818609,2020,A .Location in patent: Paragraph 0077-0080; 0134; 0139; 0140

10
[ 3987-92-6 ]
[ 790254-22-7 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synthesis,2006,p. 3467 - 3477
[3]Synlett,2005,p. 3071 - 3074
[4]Synlett,2005,p. 3071 - 3074

11
[ 3987-92-6 ]
[ 881909-54-2 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

12
[ 3987-92-6 ]
[ 790254-88-5 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

13
[ 3987-92-6 ]
[ 881909-48-4 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

14
[ 3987-92-6 ]
[ 790254-20-5 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

15
[ 3987-92-6 ]
7-Bromo-3-[((E)-but-2-enyl)oxy]-2-((E)-propenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

16
[ 3987-92-6 ]
[ 790254-16-9 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

17
[ 3987-92-6 ]
[ 790254-17-0 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synlett,2005,p. 3071 - 3074

18
[ 3987-92-6 ]
methyl 4-bromo-1-hydroxy-2-[(E)-prop-1-enyl]-1H-benzimidazole-6-carboxylate [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477

19
[ 3987-92-6 ]
methyl 4-bromo-1-hydroxy-2-[(Z)-prop-1-enyl]-1H-benzimidazole-6-carboxylate [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477

20
[ 3987-92-6 ]
methyl 4-amino-3-nitro-5-vinylbenzoate [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synthesis,2006,p. 3467 - 3477

21
[ 3987-92-6 ]
methyl 4-amino-3-(1-methylenepropyl)-5-nitrobenzoate [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477

22
[ 3987-92-6 ]
[ 883243-08-1 ]

Reference： [1]Synthesis,2006,p. 3467 - 3477

23
[ 3987-92-6 ]
methyl 7-nitro-3-propyl-1H-indole-5-carboxylate [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477
[2]Synthesis,2006,p. 3467 - 3477

24
[ 3987-92-6 ]
methyl 7-nitro-2-propyl-1H-indole-5-carboxylate [ No CAS ]

Reference： [1]Synthesis,2006,p. 3467 - 3477

25
[ 3987-92-6 ]
[ 928850-34-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

26
[ 3987-92-6 ]
[ 928850-36-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

27
[ 3987-92-6 ]
C₁₆H₁₆N₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

28
[ 3987-92-6 ]
C₁₅H₁₄N₂O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

29
[ 3987-92-6 ]
[ 928850-27-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

30
[ 3987-92-6 ]
methyl 4-(benzylamino)-3-guanidinobenzoate trifluoroacetate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

31
[ 3987-92-6 ]
C₁₅H₁₆N₄O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119

32
[ 3987-92-6 ]
[ 68502-22-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2106 - 2119
[2]Chemical Biology and Drug Design,2019,vol. 93,p. 617 - 627

33
[ 3987-92-6 ]
7-bromo-3-hydroxy-2-propenyl-3H-benzoimidazole-5-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Synlett,2005,p. 3071 - 3074

34
[ 3987-92-6 ]
[ 121649-63-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1988,vol. 27,p. 1106 - 1109

35
[ 3987-92-6 ]
[ 35532-08-2 ]

Reference： [1]Journal of the Chemical Society,1957,p. 2197,2199

36
[ 3987-92-6 ]
[ 111529-69-2 ]

Reference： [1]Journal of the Chemical Society,1957,p. 2197,2199

37
[ 3987-92-6 ]
[ 132984-46-4 ]

Reference： [1]Journal of the Chemical Society,1957,p. 2197,2199

38
[ 3987-92-6 ]
[ 110336-03-3 ]

Reference： [1]Journal of the Chemical Society,1957,p. 2197,2199

39
[ 3987-92-6 ]
methyl 4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 8 Synthesis of methyl 4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-nitrobenzoate (Compound 8) In the same manner as in Example 6, 146 mg of the title compound was obtained as yellow powder from 122 mg of <strong>[3987-92-6]methyl 4-amino-3-nitrobenzoate</strong>. Melting point: 164-165 C. 1H-NMR (CDCl3): delta 2.47 (3H, s), 3.84 (3H, s), 7.56 (1H, d, J=8.6 Hz), 7.57 (1H,brd,J=8.6 Hz), 8.01 (1H, d, J=1.8 Hz), 8.06 (1H, d, J=8.6 Hz), 8.07 (1H,brd,J=8.6 Hz), 8.25 (1H, d, J=1.8 Hz). IR numax (KBr): 3442, 3237, 3060, 2949, 1732, 1621, 1535, 1507, 1440, 1 356, 1297, 1164, 1106 cm-1.

Reference： [1]Patent: US2003/229126,2003,A1 .Location in patent: Page 14

40
[ 24424-99-5 ]
[ 3987-92-6 ]
[ 327046-64-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	Example 7 Production of N-t-butoxycarbonyl-<strong>[3987-92-6]4-methoxycarbonyl-2-nitroaniline</strong> 0.57 g of sodium hydride (60% content) was suspended in 9.87 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 9.86 g of a tetrahydrofuran solution containing 0.95 g of <strong>[3987-92-6]4-methoxycarbonyl-2-nitroaniline</strong> was added, stirred for 10 minutes, allowed to stand at room temperature and stirred for 1 hour. To the obtained mixture, 2.67 g of a tetrahydrofuran solution containing 1.30 g of di-t-butyl dicarbonate was added at a room temperature and stirred for 3 hours. The reaction mixture was added to an ice-cooled aqueous saturated ammonium chloride solution and extracted with toluene to separate an organic layer and then the organic layer was analyzed by high performance liquid chromatography to find the yield of the desired product was 80%.

Reference： [1]Patent: EP1172356,2002,A1 .Location in patent: Page 8
[2]Patent: US2002/16506,2002,A1

41
[ 24424-99-5 ]
[ 3987-92-6 ]
[ 7087-68-5 ]
[ 327046-64-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With dmap; In dichloromethane;	Part 2. To a chilled suspension of <strong>[3987-92-6]methyl 4-amino-3-nitrobenzoate</strong> (2.56 g, 11 mmol) and 4-dimethylaminopyridine (68 mg, 0.56 mmol) in CH2Cl2 (40 mL) and N,N-diisopropyl-ethylamine (1.9 mL, 11 mmol) was added a solution of di-tert-butyldicarbonate (2.2 g, 10 mmol) in CH2Cl2 (20 mL) dropwise over 20 min. The suspension was stirred at room temperature for 2 hours. Another solution of di-tert-butyldicarbonate (1.2 g, 5.5 mmol) in CH2Cl2 (10 mL) was added, and the resulting solution was stirred for another hour. The reaction was then concentrated, diluted with ethyl acetate, washed with 5% citric acid, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using 5% ethyl acetate in CH2Cl2 as eluent to yield methyl 4-[(tert-butoxy)carbonylamino]-3-nitrobenzoate (2.4 g, 74%). 1H NMR (CDCl3) delta: 1.54 (s, 9H); 3.93 (s, 3H); 8.19-8.22 (d, 1H); 8.66-8.68 (d, 1H); 8.86 (s, 1H); 9.87 (s, 1H).

Reference： [1]Patent: US6534535,2003,B1

42
[ 1588-83-6 ]
[ 3987-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In methanol; 5,5-dimethyl-1,3-cyclohexadiene; water;	a. Esterification of 4-amino-3-nitrobenzoic Acid To a 2 L 3-necked flask fitted with a mechanical stirrer are added 700 mL of methanol, 20 g of xylene, 14 g concentrated sulfuric acid and 100 g of 4-amino-3-nitrobenzoic acid. The solution is heated to reflux for 33 hours. The mixture is cooled to 35 C. and neutralized to pH 7.8. Water (1 L) is added, the solid collected and washed with 500 ml to give after drying overnight 100.9 g of methyl 4-amino-3-nitrobenzoate.

Reference： [1]Patent: US6166218,2000,A

43
[ 3987-92-6 ]
[ 78-84-2 ]
[ 1072139-13-9 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 9675 - 9684
[2]Tetrahedron Letters,2017,vol. 58,p. 4717 - 4720

44
[ 3987-92-6 ]
[ 205652-97-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 6995 - 7004
[2]Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences,2019,vol. 1114-1115,p. 86 - 92

45
[ 53178-59-9 ]
[ 3987-92-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 6995 - 7004

46
[ 3987-92-6 ]
[ 77-78-1 ]
[ 36242-50-9 ]

Yield	Reaction Conditions	Operation in experiment
97%		(Intermediate Example 69) 1-Methyl-1H-benzimidazole-5-carboxylic acid Methyl 4-amino-3-nitrobenzoate (7.0 g), sodium hydroxide (5.7 g), potassium carbonate (4.9 g) and tetrabutylammonium bromide (0.22 g) were suspended in toluene (100 ml). The mixture was stirred for 1 hour at 40C, and then dimethylsulfuric acid (7. 7 ml) was added thereto and stirred for 2 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure to give methyl 4-methylamino-3-nitrobenzoate (7.3 g, Y.: 97%). 1H NMR; (DMSO-d6) delta (ppm): 3.0 (d, 3H), 3.8 (s, 3H), 7.0 (d, 1H), 8.00 (dd, 1H), 8.5-8.7 (brs, 1H), 8.6 (d, 1H). ESI/MS (m/z): 325 (M+H)+, 323 (M-H)-.

Reference： [1]Patent: EP1595866,2005,A1 .Location in patent: Page/Page column 26

47
[ 3987-92-6 ]
[ 63189-97-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6156 - 6174

48
[ 3987-92-6 ]
[ 1448350-06-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6156 - 6174

49
[ 3987-92-6 ]
[ 1448350-19-3 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6156 - 6174

50
[ 3987-92-6 ]
[ 1448350-12-6 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6156 - 6174

51
[ 3987-92-6 ]
[ 1448350-13-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6156 - 6174

52
[ 696-59-3 ]
[ 3987-92-6 ]
[ 937601-90-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	With acetic acid; for 2h;Reflux;	General procedure: A 100-mL round-bottomed single-neck flask equipped with a condenser and a magnetic stir bar was charged with appropriated 4-substituted-2-nitroaniline (25.0mmol), 2,5-dimethoxytetrahydofurane (25.0mmol) and 40mL of glacial acetic acid. The flask was refluxed until disappearance of starting material (ca. 2 h). After the reaction mixture was cooled to rt, removal of the volatiles under reduced pressure gave the crude product which was purified by column-chromatography (Petroleum Ether/EtOAc=9:1 then 7:3) to give the desired 1-(4-substituted-2-nitrophenyl)-1H-pyrrole.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 83,p. 26 - 35

53
[ 3987-92-6 ]
[ 117007-77-9 ]
methyl 4-((4-formyl-1-methyl-1H-pyrazol-5-yl)amino)-3-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium hydroxide; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere;	General procedure: A magnetically stirred solution of pyrazole 4 (500 mg, 3.46 mmol) in DMF (7 mL)was treated with KOH (387 mg, 6.90 mmol) and nitroaniline 7a-e, 10 or 13a-b (3equiv., 10.38 mmol) then heated at 100 C for 1 h. The resulting mixture was cooledto room temperature then treated with NH4Cl (100 mL of a saturated aqueoussolution) and extracted with ethyl acetate (3 × 25 mL). The combined organic phaseswere washed with brine (1 × 50 mL) before being dried (MgSO4), filtered andconcentrated under reduced pressure to afford a yellow oil. Subjection of this residueto flash column chromatography (silica, 1:4 ? 1:1 v/v ethyl acetate/n-hexane gradientelution) and concentration of the relevant fractions afforded the target pyrazole 8a-e,11 or 14a-b.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 4568 - 4571

54
[ 65766-32-7 ]
[ 3987-92-6 ]
methyl 4-((6-(methylamino)pyrimidin-4-yl)amino)-3-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 110℃; for 16h;Sealed tube; Inert atmosphere;	b. methyl 4-((6-(methyl mino)pyrimidin-4-yl)amino)-3-nitrobenzoate 6-chloro-N-methylpyrimidin-4-amine, 3 (3g, 20.97mrnol) and <strong>[3987-92-6]methyl 4-amino-3-nitrobenzoate</strong> (3.9g, 20.97mmol) were taken in toluene (5mL) in a seal tube under Argon atmosphere at room temperature. The Argon gas was purged for 5-10 min. Then Cs2C03 (17.0g, 52.4mmol) and Xantphos (3.6g, 6.29mmol) were added and the resulting reaction mixture was purged with argon gas for 5 min, followed by Pd2(dba)3 (3.8g, 4.19mmol) was added. The argon gas purging was continued for additional 5 min before sealing the reaction vial. Then the reaction mixture was heated at 110 C for 16h. After completion of the reaction by TLC, the reaction mixture was cooled to rt, filtered through celite bed and the filtrate was evaporated under vacuum to get a crude residue. The crude residue was purified by column chromatography on silica gel to afford the title compound (3.2g, yield: 51%) as a solid; MS (ESI): 304.2 [M+H]+.

Reference： [1]Patent: WO2015/57938,2015,A1 .Location in patent: Page/Page column 102

55
[ 3987-92-6 ]
(6-chloropyrimidin-4-yl)(methyl)carbamoyl-(2,6-dichloro-3,5-dimethoxyphenyl)carbamic acid tert-butyl ester [ No CAS ]
methyl 4-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-tert-butyl carbonate ureido)pyrimidin-4-yl)amino)-3-nitrobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 12h;Sealed tube; Inert atmosphere;	b. methyl 4-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-methyl~3-tert-butyl carbonate ureido)pyrimidin~4~yl)amino)-3-nitrobenzoate Methyl 4-amino-3-nitrobenzoate (0.956g, 0.004mol) and l-(6-chloropyrimidin-4-yl)-3-(2,6- dichloro-3,5-dimethoxyphenyl)-l-methyl-3-/ert-butyl caronate urea (2g, 0.004mol) were taken in iOmL of dry toluene in a seal tube at room temperature and Argon gas was purged for 5-10 min. Then Cs2C03 (3.25g, O.Olmol) and Xantphos (0.46g, 0,0008 mol) were added and the resulting reaction mixture was purged with argon gas for 5 min, followed by Pd2(dba)3 (0.36g, 0.0004mol) was added. The argon gas purging was continued for additional 5 min before sealing the reaction vial. Then the reaction mixture was heated at 100 C for 12h. After completion of the reaction by TLC, reaction mass was filtered through celite and the fllterate was evaporated under vacuum to get a crude residue. The crude residue was purified by column chromatography on silica gel to afford the title compound (2.10g, yield: 79%); 1H-NMR (CDC13, 300MHz): delta 10.3 (s, 1H), 9.00- 8.95 (m, 2H), 8.75 (s, 1H), 8.22 (dd, 1H), 7.63 (s, 1H), 6.61 (s, 1H), 3.95 (s, 6H), 3.94 (s, 3H), 3.67 (s, 3H), 1.39 (s, 9H).

Reference： [1]Patent: WO2015/57938,2015,A1 .Location in patent: Page/Page column 98

56
[ 3987-92-6 ]
methyl 4-((tert-butoxycarbonyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-tert-butyl ureido)pyrimidin-4-yl)amino)-3-nitrobenzoate [ No CAS ]